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ABSTRACT: Mitochondrial dysfunction plays a primary role in the pathogenesis of Parkinson's disease (PD), particularly in autosomal recessive forms of the disease caused by mutations encoding PINK1. Although mitochondrial pathology can be demonstrated in many cell types, it is neurons that bear the brunt of cell death in PD. We studied the mitochondrial physiology of neurons and muscle cells with loss of function of the nuclear encoded mitochondrial protein PINK1. PINK1 is widely expressed in many types of tissues, but deficiency selectively induces death in neurons. We report here that the same genetic defect results in opposing phenotypes in different cell types, depending on the metabolic properties of the cell. Thus, PINK1-deficient myocytes exhibit high basal mitochondrial membrane potential (Δψm), whereas PINK1-deficient neurons have been shown to exhibit a low Δψm. PINK1 deficiency induces impaired respiration in both cell types, with a concomitant increase in glycolytic activity. We demonstrate that the high glycolytic capacity in myocytes compared with neurons enables them to produce more ATP and, therefore, compensates for the metabolic defects induced by PINK1 deficiency. Furthermore, the high Δψm generated in PINK1 knockout (KO) muscle mitochondria enables them to buffer cytosolic Ca(2+) fluxes, rendering them resistant to Ca(2+) stress effectively. Conversely, PINK1 KO neurons were previously shown to develop mitochondrial Ca(2+) overload and Ca(2+)-induced mitochondrial depolarisation. Prevention of Ca(2+) dysregulation in myocytes might therefore account for the sparing of these cells in PD.
Journal of Cell Science 12/2011; 124(Pt 24):4194-202. · 6.11 Impact Factor
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Emma Deas, Helene Plun-Favreau,
Sonia Gandhi,
Howard Desmond,
Svend Kjaer,
Samantha H Y Loh,
Alan E M Renton,
Robert J Harvey,
Alexander J Whitworth,
L Miguel Martins,
Andrey Y Abramov,
Nicholas W Wood
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ABSTRACT: Mutations in PTEN-induced kinase 1 (PINK1) cause early onset autosomal recessive Parkinson's disease (PD). PINK1 is a 63 kDa protein kinase, which exerts a neuroprotective function and is known to localize to mitochondria. Upon entry into the organelle, PINK1 is cleaved to produce a ∼53 kDa protein (ΔN-PINK1). In this paper, we show that PINK1 is cleaved between amino acids Ala-103 and Phe-104 to generate ΔN-PINK1. We demonstrate that a reduced ability to cleave PINK1, and the consequent accumulation of full-length protein, results in mitochondrial abnormalities reminiscent of those observed in PINK1 knockout cells, including disruption of the mitochondrial network and a reduction in mitochondrial mass. Notably, we assessed three N-terminal PD-associated PINK1 mutations located close to the cleavage site and, while these do not prevent PINK1 cleavage, they alter the ratio of full-length to ΔN-PINK1 protein in cells, resulting in an altered mitochondrial phenotype. Finally, we show that PINK1 interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) and that loss of PARL results in aberrant PINK1 cleavage in mammalian cells. These combined results suggest that PINK1 cleavage is important for basal mitochondrial health and that PARL cleaves PINK1 to produce the ΔN-PINK1 fragment.
Human Molecular Genetics 03/2011; 20(5):867-79. · 7.64 Impact Factor
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ABSTRACT: The role of mitochondria in sporadic Parkinson's disease (PD) has been debated for a little over 20 years since the description of complex I deficiency in the substantia nigra pars compacta (SNpc) of PD patients. However, the identification of recessive pathogenic mutations in the pink1 gene in familial PD cases firmly re-ignited interest in the pathophysiology of mitochondria in PD. PINK1 is a putative mitochondrial serine/threonine kinase, which protects cells against oxidative stress induced apoptosis. The mechanism by which this is achieved and the effect of the pathogenic mutations has been an area of intensive research over the past five years. Significant progress has been made and, in this review, we summarize the physiological roles that have been assigned to PINK1 and the potential mechanisms behind pathogenesis.
EMBO Molecular Medicine 06/2009; 1(3):152-65. · 10.33 Impact Factor
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Sonia Gandhi,
Alison Wood-Kaczmar,
Zhi Yao, Helene Plun-Favreau,
Emma Deas,
Kristina Klupsch,
Julian Downward,
David S Latchman,
Sarah J Tabrizi,
Nicholas W Wood,
Michael R Duchen,
Andrey Y Abramov
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ABSTRACT: Mutations in PINK1 cause autosomal recessive Parkinson's disease. PINK1 is a mitochondrial kinase of unknown function. We investigated calcium homeostasis and mitochondrial function in PINK1-deficient mammalian neurons. We demonstrate physiologically that PINK1 regulates calcium efflux from the mitochondria via the mitochondrial Na(+)/Ca(2+) exchanger. PINK1 deficiency causes mitochondrial accumulation of calcium, resulting in mitochondrial calcium overload. We show that calcium overload stimulates reactive oxygen species (ROS) production via NADPH oxidase. ROS production inhibits the glucose transporter, reducing substrate delivery and causing impaired respiration. We demonstrate that impaired respiration may be restored by provision of mitochondrial complex I and II substrates. Taken together, reduced mitochondrial calcium capacity and increased ROS lower the threshold of opening of the mitochondrial permeability transition pore (mPTP) such that physiological calcium stimuli become sufficient to induce mPTP opening in PINK1-deficient cells. Our findings propose a mechanism by which PINK1 dysfunction renders neurons vulnerable to cell death.
Molecular cell 04/2009; 33(5):627-38. · 14.61 Impact Factor
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ABSTRACT: Rare, inherited mutations causing familial forms of Parkinson's disease have provided insight into the molecular mechanisms that underlie the genetic and sporadic forms of this disease. Loss of protein function resulting from autosomal-recessive mutations in PTEN-induced putative kinase 1 (PINK1), Parkin and DJ-1 has been linked to mitochondrial dysfunction, accumulation of abnormal and misfolded proteins, impaired protein clearance and oxidative stress. Accumulating evidence suggests that wild-type PINK1, Parkin and DJ-1 may be key components of neuroprotective signalling cascades that run in parallel, interact via cross talk or converge in a common pathway.
FEBS Journal 01/2009; 275(23):5758-66. · 3.79 Impact Factor
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ABSTRACT: Parkinson's disease (PD) is a common, disabling, neurodegenerative disease. Our knowledge of the molecular events leading to PD is being greatly enhanced by the study of relatively rare familial form of the disease. Nevertheless, the pathways leading from the genetic mutations to nigral cell degeneration and the other features in PD remain poorly understood. The identification of PINK1, a mitochondrial putative protein kinase, has helped understand the pathophysiology of mitochondria and their potential role in PD. Mutations in PINK1 are associated with the PARK6 autosomal recessive, early-onset, PD-susceptibility locus. Point mutations in another mitochondrial protein, HtrA2, are a susceptibility factor for PD (PARK13 locus). We report here the results of investigations into the interactors and pathways of these two mitochondrial molecules (PINK1 and HtrA2) in a range of models and human PD tissue.
Annals of the New York Academy of Sciences 01/2009; 1147:30-6. · 3.15 Impact Factor
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ABSTRACT: Rare, inherited mutations causing familial forms of Parkinson’s disease have provided insight into the molecular mechanisms that underlie the genetic and sporadic forms of this disease. Loss of protein function resulting from autosomal-recessive mutations in PTEN-induced putative kinase 1 (PINK1), Parkin and DJ-1 has been linked to mitochondrial dysfunction, accumulation of abnormal and misfolded proteins, impaired protein clearance and oxidative stress. Accumulating evidence suggests that wild-type PINK1, Parkin and DJ-1 may be key components of neuroprotective signalling cascades that run in parallel, interact via cross talk or converge in a common pathway.
FEBS Journal 11/2008; 275(23):5758 - 5766. · 3.79 Impact Factor
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Proceedings of the National Academy of Sciences 09/2008; 105(32):11041-2. · 9.68 Impact Factor
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Karsten M Strauss,
L Miguel Martins, Helene Plun-Favreau,
Frank P Marx,
Sabine Kautzmann,
Daniela Berg,
Thomas Gasser,
Zbginiew Wszolek,
Thomas Müller,
Antje Bornemann,
Hartwig Wolburg,
Julian Downward,
Olaf Riess,
Jörg B Schulz,
Rejko Krüger
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ABSTRACT: Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.
Human Molecular Genetics 09/2005; 14(15):2099-111. · 7.64 Impact Factor
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Helene Plun-Favreau,
Kristina Klupsch,
Sonia Gandhi,
Svend Kjaer,
David Frith,
Kirsten Harvey,
Emma Deas,
Robert J Harvey,
Neil McDonald,
Nicholas W Wood,
L Miguel Martins,
Julian Downward
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ABSTRACT: This is the authors' final draft of the version published as Nature Cell Biology, 2007, 9 (11), pp.1243-52. The final published version is available online at http://www.nature.com/ncb/journal/v9/n11/full/ncb1644.html
